Safety and Dose-Finding Study of DTX301 (scAAV8OTC) in Adults With Late-Onset Ornithine Transcarbamylase (OTC) Deficiency (CAPtivate)

A Phase 1/2, Open-Label Safety and Dose-Finding Study of Adeno-Associated Virus (AAV) Serotype 8 (AAV8)-Mediated Gene Transfer of Human Ornithine Transcarbamylase (OTC) in Adults With Late-Onset OTC Deficiency

This is a Phase 1/2, open-label, single arm, multicenter, safety and dose finding study of DTX301 in adults with late-onset OTC deficiency. The primary objective of the study is to determine the safety of single intravenous (IV) doses of DTX301.

Study Overview

• Status: Completed
• Conditions: Ornithine Transcarbamylase (OTC) Deficiency
• Intervention / Treatment: Genetic: scAAV8OTC; Drug: Reactive Corticosteroid Taper Regimen; Drug: Prophylactic Corticosteroid Taper Regimen

Detailed Description

Eligible participants will receive a single IV infusion of DTX301. Dose escalation will be conducted according to a model that uses the collected data to predict the safety profile of the dose in order to determine the optimal biological dose (OBD). The decision to proceed to the next dose cohort will be made after the data monitoring committee (DMC) has evaluated the safety data for all participants in a dosing cohort. Participants will be followed for 52 weeks after dosing. After completion of this study, participants will be asked to enroll in a 4-year extension study to evaluate the long term (a total of 5 years) safety and efficacy of DTX301.

This study was previously posted by Dimension Therapeutics, which has been acquired by Ultragenyx.

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T3B 6A8
      • Alberta's Children's Hospital
• Spain
  • A Coruna
    • Santiago de Compostela, A Coruna, Spain, 15706
      • Hospital Clinico Universitario de Santiago
  • Vizcaya
    • Barakaldo, Vizcaya, Spain, 48903
      • Hospital Universitario de Cruzes
• United Kingdom
  • Birmingham, United Kingdom, B15 2TH
    • Queen Elizabeth Hospital
  • London City
    • London, London City, United Kingdom, WC1N 3BG
      • National Hospital for Neurology & Neurosurgery
• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • The Children's Hospital Colorado
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital
  • New York
    • New York, New York, United States, 10029-6508
      • Icahn School of Medicine at Mount Sinai
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • University Hospital Cleveland Medical Center/Case Western Reserve University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Key Inclusion Criteria:

1. Males and females ≥18 years of age with documented diagnosis of late onset (defined as first manifestation of signs and symptoms at ≥1 month of age) OTC deficiency, confirmed via enzymatic, biochemical, or molecular testing
2. Documented history of ≥1 symptomatic hyperammonemia event with ammonia ≥100 µmol/L.
3. Subject's OTC deficiency is stable as evidenced by either a) no clinical symptoms of hyperammonemia OR b) an ammonia level <100 µmol/L within the 4 week period preceding the Screening visit.
4. On ongoing daily stable dose of ammonia scavenger therapy for ≥4 weeks.
5. Males and all females of childbearing potential must be willing to use effective contraception at the time of administration of gene transfer and for the 52 weeks following administration of DTX301

Key Exclusion Criteria:

1. At Screening or Baseline (Day 0), plasma ammonia level ≥ 100 μmol/L for patients who historically maintain normal ammonia levels; OR plasma ammonia level ≥ 200 μmol/L for patients who historically are not able to fully control ammonia levels with baseline management; OR signs and symptoms of hyperammonemia.
2. Liver transplant, including hepatocyte cell therapy/transplant.
3. History of liver disease
4. Significant hepatic inflammation or cirrhosis
5. Serum creatinine >2.0 mg/dL.
6. Participation in another investigational medicine study (including another gene transfer trial) within 3 months of Screening
7. Pregnant or nursing

Note additional inclusion/exclusion criteria may apply, per protocol.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1: DTX301 2.0 × 10^12 GC/kg; DTX301 (scAAV8OTC) 2.0 × 10^12 GC/kg will be administered as a single peripheral IV infusion. A reactive corticosteroid taper regimen will be administered to control transient vector-induced hepatic effects. Sodium acetate will be used as a tracer to measure the rate of ureagenesis.	Genetic: scAAV8OTC; non-replicating, recombinant scAAV8 encoding human ornithine transcarbamylase (OTC); Other Names: DTX301; Drug: Reactive Corticosteroid Taper Regimen; Oral prednisone [or oral prednisolone] 60 mg/day week 1, 40 mg/day Week 2, 30 mg/day Weeks 3 and 4, tapered by 5 mg/week Week 5 and beyond until liver enzymes return to baseline levels. Corticosteroid treatment will be considered when a participant's alanine aminotransferase (ALT) level exceeded the upper limit of normal (ULN) and the ALT increase was considered by the Investigator to be related to DTX301.
Experimental: Cohort 2: DTX301 6.0 × 10^12 GC/kg; DTX301 (scAAV8OTC) 6.0 × 10^12 GC/kg will be administered as a single peripheral IV infusion. A reactive corticosteroid taper regimen will be administered to control transient vector-induced hepatic effects. Sodium acetate will be used as a tracer to measure the rate of ureagenesis.	Genetic: scAAV8OTC; non-replicating, recombinant scAAV8 encoding human ornithine transcarbamylase (OTC); Other Names: DTX301; Drug: Reactive Corticosteroid Taper Regimen; Oral prednisone [or oral prednisolone] 60 mg/day week 1, 40 mg/day Week 2, 30 mg/day Weeks 3 and 4, tapered by 5 mg/week Week 5 and beyond until liver enzymes return to baseline levels. Corticosteroid treatment will be considered when a participant's alanine aminotransferase (ALT) level exceeded the upper limit of normal (ULN) and the ALT increase was considered by the Investigator to be related to DTX301.
Experimental: Cohort 3: DTX301 1.0 × 10^13 GC/kg; DTX301 (scAAV8OTC) 1.0 × 10^13 GC/kg will be administered as a single peripheral IV infusion. A reactive corticosteroid taper regimen will be administered to control transient vector-induced hepatic effects. Sodium acetate will be used as a tracer to measure the rate of ureagenesis.	Genetic: scAAV8OTC; non-replicating, recombinant scAAV8 encoding human ornithine transcarbamylase (OTC); Other Names: DTX301; Drug: Reactive Corticosteroid Taper Regimen; Oral prednisone [or oral prednisolone] 60 mg/day week 1, 40 mg/day Week 2, 30 mg/day Weeks 3 and 4, tapered by 5 mg/week Week 5 and beyond until liver enzymes return to baseline levels. Corticosteroid treatment will be considered when a participant's alanine aminotransferase (ALT) level exceeded the upper limit of normal (ULN) and the ALT increase was considered by the Investigator to be related to DTX301.
Experimental: Cohort 4: DTX301 1.0x10^13 GC/kg + Prophylactic Corticosteroids; A prophylactic corticosteroid taper regimen (oral prednisone [or prednisolone], 60 mg tapered over 9 weeks) will be administered before dosing with DTX301 (scAAV8OTC) to prevent or minimize transient vector-induced hepatic effects. DTX301 (scAAV8OTC) 1.0x10^13 GC/kg administered as a single peripheral IV infusion. Sodium acetate will be used as a tracer to measure the rate of ureagenesis.	Genetic: scAAV8OTC; non-replicating, recombinant scAAV8 encoding human ornithine transcarbamylase (OTC); Other Names: DTX301; Drug: Prophylactic Corticosteroid Taper Regimen; Oral prednisone [or oral prednisolone] 60 mg/day at least 5 days prior to DTX301 administration, tapered over 9 weeks. A prophylactic corticosteroid taper regimen will be administered to prevent or minimize transient vector-induced hepatic effects.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Adverse Events (AEs), Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and TEAEs Leading to Discontinuation	AE: any untoward medical occurrence regardless of its causal relationship to study product. TEAE: any event not present before exposure to study product or any event already present that worsens in either intensity or frequency after exposure to study product. SAE: any event that results in death; is immediately life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; results in a congenital anomaly/birth defect; is an important medical event, according to the investigator. AE intensity was rated as Grade 1 (mild), 2 (moderate), 3 (severe), 4 (life threatening), or 5 (death) according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE). The relationship or association of the study product in causing or contributing to the AE was characterized as: unrelated; possible; probably; definite.	AEs Prior to Dosing: From signing the informed consent form (ICF) to first dose of study drug. TEAEs: From first dose of study drug up to End of Study (Week 52).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline Over Time in Rate of Ureagenesis	The change from baseline in the rate of ureagenesis (as measured by the generation of [13C]urea over 4 hours) as determined by gas chromatography mass spectrometry over time to 52 weeks after the IV administration of DTX301. Sodium acetate was used as a tracer to measure the rate of ureagenesis. Rate of ureagenesis was derived in the following manner: Derive area under the curve from time zero to 240 minutes (AUC0-240min) of absolute 13C-urea (µmol/l/min) estimated by the linear trapezoidal rule; Derive percent of normal AUC0-240min of absolute 13C-urea by dividing AUC0-240min of absolute 13C-urea (µmol*min/L) by 669.56 µmol*min/L (i.e. the AUC0-240min of absolute 13C-urea for an adult control); Derive rate of ureagenesis by multiplying % of normal AUC0-240min of absolute 13C-urea by 300 µmol*h/kg (i.e. the approximate rate of ureagenesis in healthy adults).	Baseline (Day 0), Weeks 6, 12, 20, 24, End of Study (Week 52). AUC was derived based on the following time points: 0.5, 1, 1.5, 2, 3, and 4 hours postdose.
Change From Baseline Over Time in Area Under the Curve From Time Zero to 24 Hours (AUC0-24) of Plasma Ammonia		Baseline (Day 0), Weeks 6, 12, 24, End of Study (Week 52). AUC was derived based on predose (time 0) and approximately 2, 4, 8, 12, 16, 20, 24 hours (±5 minutes) postdose.

Collaborators and Investigators

• Sponsor: Ultragenyx Pharmaceutical Inc

Study record dates

Study Major Dates

• Study Start (Actual): July 31, 2017
• Primary Completion (Actual): December 16, 2021
• Study Completion (Actual): December 16, 2021

Study Registration Dates

• First Submitted: December 9, 2016
• First Submitted That Met QC Criteria: December 12, 2016
• First Posted (Estimate): December 13, 2016

Study Record Updates

• Last Update Posted (Estimate): January 26, 2023
• Last Update Submitted That Met QC Criteria: January 23, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: Gene Transfer; OTC Deficiency; Urea Cycle Disorder
• Other Study ID Numbers: 301OTC01; 2016-001057-40 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No